As the inventor has determined, N-aminoacyl)amino acids, on the basis of their release of dopamine, lead to increased blood flow, both centrally and peripherally. Up till now agents belonging to the group of N-(aminoacyl)amino acids (known as angiotensin-converting enzyme inhibitors or ACE-inhibitors) have been used as drugs for lowering blood pressure.
An increased noradrenaline content contributes to high blood pressure. It is known that ACE-inhibitors lower blood pressure by inhibiting the formation of angiotensin II. In this connection some experts discuss a small reduction of the noradrenaline. Noradrenaline, however, is formed from dopamine and therefore hitherto one had to expect that in any reduction of noradrenaline there would also be a lowering of dopamine.
In tests of the inventor it has now been unexpectedly established that the opposite occurs: when administering N-(aminoacyl)amino acids, a highly significant rise of dopamine occurs. On the basis of this release of dopamine (dopaminergic effect), the administration of the above noted compounds leads to a cerebral and peripheral increase of blood flow; this is surprising against the known background.
It is known that in the case of blood flow disorders in patients having low blood pressure, dopamine can be used for stabilizing blood circulation. The tests of the inventor show that by using N-(aminoacyl)-amino acids with patients used in the present tests who have low blood pressure, there is no further lowering of the blood pressure; instead, there is an increased central and peripheral blood flow.
This effect can be detected cerebrally: the dopaminergic action is identifiable and demonstrable in the brain by means of neurotransmitter changes according to the method developed by the inventor (Dr. G Weth, "Das Verhalten der Neurotransmitter . . . " [The Behavior of Neurotransmitters . . . ], a dissertation, University of Wurzburg 1987, pages 123-138). Tests on patients to whom N-(aminoacyl)-amino acids had been administered sublingually showed a centrally detectable dopaminergic effect.
An increase of blood flow with N-(mercaptoacyl)-amino acids is known from the DE-OS 39 32 749 (published on Apr. 11, 1991) and from the EP-A 498 899 (published on Aug. 19, 1992), both in the name of the present inventor. These compounds, however, have a different structure from the N-(aminoacyl)-amino acids used according to the present invention.
Moreover, the effect of ACE-inhibitors in respect of lowering prolactin in the plasma has been described in various works. These works and literature passages of which the inventor has further become aware are as follows: Journal of Biological Regulators and Homeostatic Agents, Volume 3, No. 3, July-September 1989, pages 128-129, Milano, IT, C. Lombardi et al; Minerva Medica, Volume 81, No. 9, September 1990, pages 587-590, IT, C. Lombardi et al; J.E.F. Reynolds et al: Martindale, the Extra Pharmacopoeia, Ed. 29, 1989, the Pharmaceutical Press, pages 478-480, London, GB, Summary 12969-e: enalapril maleate; J.E.F. Reynolds et al: Martindale, the Extra Pharmacopoeia, Ed. 29, 1989, the Pharmaceutical Press, page 493, London, GB, Summary 729-s: perindopril; The Journal of Clinical Endocrinology & Metabolism, Volume 64, No. 4, April 1987, pages 713-717, The Endocrine Society, U.S., W. B. Malarkey et al.; Angiology, Volume 41, No. 5, May 1990, pages 377-381, New York, U.S., I. Saito et al, Summary, page 379, Figure 1; Prolactin, Basic and Clinical Correlates, Volume 1, 1985, pages 53-57, Liviana Press, Padova, IT, C. Denef; J.E.F. Reynolds et al., publisher Martindale, the Extra Pharmacopoeia, Ed. 29, 1989, pages 468-472, London, GB, paragraph 856-C: captopril; Fuchs, J. et al.: 2-Mercapto-propionylglycine and Related Compounds in Treatment of Mitochondrial Dysfunction and Postichemic Myocardial Damage in: Arzneim.-Forsch./Drug Research 35 (II), No. 9, 1985, pages 1394-1402; Yambuchi, H. et al.: General Pharmacological Properties of the Potent Angiotensin Converting Enzyme Inhibitor Rentiapril, in: Arzneim.-Forsch./Drug Res. 37 (I), No. 2, 1987, pages 157-164; Takada, Toyokazu et al.: Effects of an Angiotensin I-Converting Enzyme Inhibitor (SA-446) on Renal Function on Dogs, in: Japan J. Pharmacol. 38, 1985, pages 227-230; Studies on Mechanisms of Antinephritic Action of SA-445, an Angiotensin I Converting Enzyme Inhibitor (1) a comparison with Actions of Spironolactone, Kallidionogenase and Saralacin, in: Japanese J. Parmacol. 42, 1986, pages 465-475; U.S. Pat. Nos. 4,046,889; 4,316,906, EP-A-366 033.
The tests indicated hereinafter show that an effect of clearly increasing blood flow occurs due to administering N-(aminoacyl)-amino acids.
An increase of blood flow was demonstrated in a video-film. It is possible to show by means of a video-film that after administering the substances described hereinafter, there occurs a distinct increase, of more than 50%, of blood flow. Additionally, it is shown that also in the case of decreased blood flow (either caused by drugs or by atherosclerosis), there occurs an obvious (up to a five-fold) increase within one minute after an intravenous administration of these substances.